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The Journal of Immunology, 2007, 178: 2651-2654.
Copyright © 2007 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Oseltamivir Decreases T Cell GM1 Expression and Inhibits Clearance of Respiratory Syncytial Virus: Potential Role of Endogenous Sialidase in Antiviral Immunity1

Martin L. Moore*, Michael H. Chi*, Weisong Zhou*, Kasia Goleniewska*, Jamye F. O’Neal*, James N. Higginbotham{dagger} and R. Stokes Peebles, Jr.2,*

* Department of Medicine and {dagger} Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
The sialoglycosphingolipid GM1 is important for lipid rafts and immune cell signaling. T cell activation in vitro increases GM1 expression and increases endogenous sialidase activity. GM1 expression has been hypothesized to be regulated by endogenous sialidase. We tested this hypothesis in vivo using a mouse model of respiratory syncytial virus (RSV) infection. RSV infection increased endogenous sialidase activity in lung mononuclear cells. RSV infection increased lung CD8+ T cell surface GM1 expression. Activated CD8+ T cells in the lungs of RSV-infected mice were GM1high. Treatment of RSV-infected mice with the sialidase/neuraminidase inhibitor oseltamivir decreased T cell surface GM1 levels. Oseltamivir treatment decreased RSV-induced weight loss and inhibited RSV clearance. Our data indicate a novel role for an endogenous sialidase in regulating T cell GM1 expression and antiviral immunity. Also, oseltamivir, an important anti-influenza drug, inhibits the clearance of a respiratory virus that lacks a neuraminidase gene, RSV.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Glycosphingolipids (GSLs),3 a diverse family of lipids that contain a ceramide backbone and a sugar chain, reside in the outer leaflet of the plasma membrane and have the capacity to associate closely with each other and with cholesterol to form "liquid-ordered" lipid microdomains, also called lipid rafts (1). In cell-to-cell signaling, lipid rafts cluster and function as cell surface signaling platforms, as in the case of the immunological synapse (2). Cell surface proteins can be associated with or excluded from lipid rafts (3).

GSLs play active roles in cell signaling. The sialoglycosphingolipid GM1 is the most commonly used marker of lipid rafts, and GM1 accumulates in the immunological synapse (4). In motile T cells, GM1 accumulates in the rear of the cell whereas GM3 accumulates in the leading edge (5). GM1 modulates opioid receptor signal transduction (6, 7). TNF-{alpha} increases GM3 synthase gene transcription and GM3 levels (8). Thus, lipid raft GSL content is tightly regulated, and GSLs play distinct roles in cellular processes.

However, mechanisms by which GSLs regulate cell signaling remain unclear. One hypothesis is that endogenous sialidases act on GSLs to modulate raft GSL content and cell signaling (9, 10). Activation of T cells in vitro induces sialidase gene expression and activity (11, 12, 13). Various GSLs are implicated as targets of endogenous sialidases (9, 10, 11, 13, 14). Mammalian sialidases predominantly act on polysialyated GSL substrates (e.g., GD1a and GT1b), and the principal reaction product is monosialyated GM1 (13, 15, 16). Activation of T cells in vitro by anti-CD3 stimulation increases surface GM1 levels (17). Thus, increased T cell GM1 levels may be mediated by endogenous sialidase acting on polysialyated GSLs.

We tested the hypothesis that an endogenous sialidase regulates T cell GM1 expression and plays an immunoregulatory role in respiratory syncytial virus (RSV) infection in vivo. RSV is the chief cause of bronchiolitis and viral pneumonia in infants. In BALB/c mice, the immune response to primary infection with the A2 strain of RSV is characterized by the influx of IFN-{gamma}-producing T cells in the lung and a robust CTL response (18, 19). We now show that RSV infection increases activated T cell GM1 expression in vivo and induces endogenous sialidase activity in lung mononuclear cells. Treatment of RSV-infected mice with the sialidase/neuraminidase (NA) inhibitor oseltamivir reduces GM1 expression on the surface of T cells, blunts RSV-induced weight loss, and inhibits viral clearance.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Virus and mice

The A2 strain of RSV was provided by R. Chanock (National Institutes of Health, Bethesda, MD). Female, 8- to 10-wk-old BALB/c (Charles River Laboratories) mice were infected intranasally with 106 PFU of RSV or mock-infected as described previously (20).

Flow cytometric analysis of lung mononuclear cells

Lungs were harvested, and mononuclear cells were isolated by Ficoll-Hypaque centrifugation. Cells were counted then treated and stained using anti-CD3, anti-CD8a, and anti-CD4 Abs (BD Pharmingen). For staining of intracellular IFN-{gamma}, cells were stimulated in RPMI 1640/10% heat-inactivated FBS/1 µM ionomycin (Sigma-Aldrich)/10 ng/ml PMA (Sigma-Aldrich)/7 µl/10 ml Golgi Stop (BD Pharmingen) for 6 h at 37°C with 5% CO2. FITC-conjugated cholera toxin B subunit (CtxB-FITC) was obtained from Sigma-Aldrich. In titration studies, we determined that 0.1 µg of CtxB-FITC per 2 x 105 cells resulted in appropriate GM1 staining. For staining RSV-specific CD8+ T cells, we used RSV M2-specific PE-conjugated H-2Kd tetramers or, as a negative control, influenza nucleoprotein-specific PE-conjugated H-2Kd tetramers (Beckman Coulter) as described previously (21). Cell samples were analyzed using a LSR II flow cytometer (BD Biosciences). Data were analyzed using WinMDI 2.8 software.

Quantitation of virus and IFN-{gamma} in lung tissue

Infectious RSV was titrated in triplicate by plaque assay on HEp-2 cells as described previously (20). Levels of IFN-{gamma} were measured in lung homogenates diluted 1:10 using an ELISA kit (R&D Systems).

Sialidase assay

Sialidase activity of lung mononuclear cells was measured in duplicate using 2'-(4-methylumbelliferyl)-{alpha}-D-N-acetylneuraminic acid (4-MUNANA) (Sigma-Aldrich) as a substrate as described previously (11). Cells were resuspended in 12 mM CaCl2 at 3 x 107 cells/ml and incubated at 37°C for 10 min. The assay buffer consisted of 100 µl of 0.2 M sodium acetate/0.2 M acetic acid (pH 5.5), 10 µl of 2 mM 4-MUNANA, and 10 µl of 10 mg/ml BSA. Eighty microliters of cells (2.4 x 106 cells), 80 µl of 12 mM CaCl2 (blank), or 0.1 U of Vibrio cholerae NA (Sigma-Aldrich) in 80 µl of 12 mM CaCl2 (positive control) were added to the assay buffer and incubated at 37°C for 45 min. The reaction was stopped by addition of 800 µl of 20 mM sodium bicarbonate (pH 10.4). The fluorescent product of sialidase cleavage of 4-MUNANA is 4-methylumbelliferone (4-MU), which was quantified in a SpectraMax M5 plate reader (Molecular Devices). The concentration of 4-MU was calculated by subtracting the value of the blank and comparing to a standard curve generated from free 4-MU (Sigma-Aldrich).

Oseltamivir treatment

Oseltamivir phosphate for oral suspension (Roche Laboratories) was reconstituted in water according to the manufacturer’s instructions. BALB/c mice were infected with RSV as described above. The mice were given water or 10 mg/kg/day oseltamivir by oral gavage 4 h preinfection and then every 12 h. Mice given 10 mg/kg/day of oseltamivir have plasma levels similar to humans given an oral dose of 75 mg twice daily (22).

Statistical analyses

Values of p were determined by a two-tailed t test, assuming equal variance. Data are representative of at least three replicate experiments in which similar results were found in all replicate experiments.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
RSV infection increases GM1 levels on CD8+ T cells in the lung

Because T cells activated in vitro have increased surface GM1 expression, we hypothesized that RSV infection would increase GM1 cell surface expression on activated T cells in vivo (17). In our hands, the peak day of lung IFN-{gamma} levels in RSV-infected BALB/c mice is 6 days postinfection (d.p.i.) (23). The peak pulmonary T cell response of BALB/c mice to primary RSV infection is 6–12 d.p.i., and the IFN-{gamma}-expressing CD8+ T cells peak earlier than RSV-specific CD8+ T cells (18, 19, 24). Thus, 6 d.p.i. represents the peak IFN-{gamma} response and the onset of the T cell response to primary RSV infection in BALB/c mice. Lung mononuclear cells were isolated from mock-infected and RSV-infected mice 6 d.p.i. We used FITC-conjugated CtxB, which specifically binds GM1, to quantify cell surface GM1 by flow cytometry (25). CtxB staining revealed GM1low and GM1high lymphocytes in the lungs of mock-infected and RSV-infected mice (Fig. 1A). RSV infection resulted in a significant increase in GM1 levels on the surface of CD8+ T cells (Fig. 1, A and B). Thus, RSV infection increased T cell GM1 expression. Similar results were observed 8 d.p.i. (data not shown). Seventy-three to 80% of IFN-{gamma}-expressing CD8+ T cells from the lungs of both mock-infected and RSV-infected mice were GM1high (Fig. 1C). RSV infection induced the accumulation of large numbers of GM1highIFN-{gamma}+ CD8+ T cells in the lung 6 d.p.i. (Fig. 1D). We hypothesized that because GM1 was an activation marker of CD8+ T cells, the GM1high CD8+ T cells would be RSV-specific. To test this hypothesis, we used RSV-specific tetramers. Virtually all RSV-specific CD8+ T cells in the lungs of RSV-infected mice were GM1high (Fig. 2). Similar results were observed 8 d.p.i. (data not shown). Thus, IFN-{gamma}-expressing and RSV-specific CD8+ T cells in the lungs of RSV-infected mice were GM1high. To our knowledge, this is the first report of increased GM1 expression in activated T cells in vivo.


Figure 1
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  		FIGURE 1. RSV infection increases CD8+ T cell GM1 expression. BALB/c mice were mock-infected (n = 5) or infected with RSV (n = 5). Lung mononuclear cells were isolated 6 d.p.i. and stained with anti-CD49b-biotin/allophycocyanin-streptavidin, anti-CD3-PerCP-Cy5.5, anti-CD8-allophycocyanin-Cy7, CtxB-FITC, and anti-IFN-{gamma}-PE-Cy7. A, Representative dot plots of GM1 staining of gated lymphocytes and gated CD8+ T cells from mock-infected and RSV-infected mice. The percentage of GM1high CD8+ T cells is indicated. B, Percentage of CD8+ T cells that were GM1high for mock-infected and RSV-infected mice. C, Representative dot plots of GM1 and IFN-{gamma} staining of CD8+ T cells from mock-infected and RSV-infected mice. D, Total number of GM1highIFN-{gamma}+ CD8+ T cells in the lungs of mock-infected and RSV-infected mice. *, p < 0.05.

 

Figure 2
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  		FIGURE 2. RSV-specific CD8+ T cells are GM1high. Lung mononuclear cells were harvested from RSV-infected mice 6 d.p.i. and stained with anti-CD3-PerCP-Cy5.5, anti-CD8-allophycocyanin-Cy7, CtxB-FITC, and either a RSV CTL epitope-loaded tetramer-PE or an influenza CTL epitope-loaded tetramer-PE as a control for specificity.

 
RSV infection induces endogenous sialidase activity in the lung

Because T cells activated in vitro have increased endogenous sialidase activity and RSV infection induces a robust T cell response in the lungs of BALB/c mice, we hypothesized that RSV infection would increase endogenous sialidase activity in lung inflammatory cells in vivo (11, 12, 13). Lung mononuclear cells were isolated from mock-infected and RSV-infected mice 6 d.p.i. RSV infection increased lung mononuclear cell endogenous sialidase activity 3.7-fold (Table I). To our knowledge, this is the first demonstration that inflammatory cell endogenous sialidase activity can be induced by viral infection.


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  		Table I. RSV infection induces endogenous sialidase activity in lung mononuclear cells

 
Oseltamivir treatment reduces GM1 levels and inhibits RSV clearance

To test the hypothesis that an endogenous sialidase is involved in T cell GM1 expression and RSV pathogenesis, we treated mice with the sialidase/NA inhibitor oseltamivir. Oseltamivir has been shown to enhance morphine analgesia in mice, and the effects of morphine are known to be modulated by GM1 and endogenous sialidase, with speculation that oseltamivir blocks GM1 synthesis by inhibiting an endogenous sialidase that targets polysialyated lipids (6, 7). Consistent with this hypothesis, oseltamivir treatment of RSV-infected mice decreased CD8+ T cell surface levels of GM1 6 d.p.i. (Fig. 3, A and B), while not altering the percentage or total number of CD8+ T cells in the lungs of RSV-infected mice that were IFN-{gamma}-expressing or RSV-specific 6 or 8 d.p.i. (data not shown). However, oseltamivir treatment inhibited clearance of infectious RSV from the lung 6 d.p.i. and reduced RSV-induced weight loss (Fig. 4, A and B). Oseltamivir had no effect on peak viral titers 4 d.p.i. (data not shown), nor modulated IFN-{gamma} levels in the lungs of RSV-infected mice 6 d.p.i. (data not shown). Taken together, these data indicate that an endogenous sialidase regulates CD8+ T cell GM1 surface levels in vivo, modulates RSV-induced illness, and promotes viral clearance.


Figure 3
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  		FIGURE 3. Treatment of RSV-infected mice with oseltamivir reduces T cell GM1 cell surface levels. RSV-infected mice were treated with water or 10 mg/kg/day of oseltamivir (five mice per group), and lungs were harvested 6 d.p.i. Whole lung mononuclear cells were stained with anti-CD3-PerCP-Cy5.5, anti-CD8-APC-Cy7, anti-CD4-PE-Cy, CtxB-FITC, and either a RSV CTL epitope-loaded tetramer-PE or an influenza CTL epitope-loaded tetramer-PE as a control for specificity. A, Representative dot plots show GM1 staining of gated CD8+ T cells. The percentage of GM1high and the GM1 mean fluorescence intensity (MFI) of gated CD8+ T cells is indicated. B, MFI of GM1 of gated CD8+ T and RSV-specific CD8+ T cells from RSV-infected mice treated with water or 10 mg/kg/day oseltamivir. *, p < 0.05.

 

Figure 4
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  		FIGURE 4. Treatment of RSV-infected mice with oseltamivir delays viral clearance and reduces RSV-induced illness. A, RSV-infected mice were treated with water or 10 mg/kg/day oseltamivir, lungs were harvested 6 d.p.i., and infectious RSV was titrated. Each symbol represents an individual mouse. The short horizontal lines represent mean titers. The dotted line at 3.3 x 103 represents the lower limit of detection of the assay. *, p < 0.05 compared with water. B, RSV-infected mice were treated with water (n = 10) or 10/mg/kg/day of oseltamivir (n = 12). Weight loss ± SEM is shown. *, p < 0.05 compared with water.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
We show that oseltamivir decreases T cell surface levels of the lipid raft-associated GM1 and inhibits antiviral effector functions in RSV infection. We also show that RSV infection induces lung mononuclear cell sialidase activity in vivo 6 d.p.i. To our knowledge, this is the first report of endogenous sialidase activity induced by viral infection in vivo. We investigated the role of endogenous sialidase in RSV pathogenesis using the sialidase inhibitor oseltamivir. Our findings suggest that oseltamivir elicits an anti-inflammatory effect by inhibiting an endogenous, T cell-associated sialidase that contributes to antiviral immunity.

Sialidases regulate T cell activation and cytokine expression. There are three known sialidases in mice and humans, neu-1, neu-2, and neu-3 (13). Neu-1 and neu-3 are induced in T cells by TCR stimulation, and these enzymes regulate T cell cytokine expression (11, 13, 26). These studies led to the hypothesis that GSL metabolism plays a role in T cell regulation and cytokine expression (10). Interestingly, it was recently reported that GM1 expression is increased in T cells from patients with systemic lupus erythematosus, a disease in which T cells play an immunopathological role (27, 28). Altering GSL metabolism and/or targeting endogenous sialidases action may provide therapeutic strategies for T cell-mediated diseases.

In BALB/c mice, RSV clearance and RSV-induced weight loss are mediated by T cells (29). Depletion of CD4+ and/or CD8+ lymphocytes delays viral clearance and has no effect on peak (4 d.p.i.) RSV titers in the lung (29). Similarly, oseltamivir treatment inhibited RSV-induced weight loss, delayed RSV clearance, and had no effect on peak viral titers. Thus, it is likely that the inhibitory effect on oseltamivir on RSV clearance is mediated, at least in part, by T cells. This hypothesis is supported by our observation that oseltamivir reduced CD8+ T cell GM1 levels. Depletion of LFA-1-expressing cells in RSV-infected BALB/c mice also delays viral clearance and reduces illness, and LFA-1 is lipid-raft-associated (30, 31).

Our data strongly suggests that oseltamivir can inhibit an endogenous sialidase. Oseltamivir blocks GM1-mediated opioid hyperalgesia induced by low doses of morphine (7). Exogenous NA increases GM1 levels on neurons in vitro, and administration of NA or GM1 to neurons enhances the ability of low-dose morphine to stimulate excitatory signaling (7). In this study, oseltamivir decreased GM1 levels on the surface of CD8+ T cells in the lungs of RSV-infected mice. Oseltamivir inhibited RSV clearance and RSV-induced illness, which, taken together with the GM1 data, suggests that the drug inhibits the T cell response to RSV infection. However, it is possible that an oseltamivir-sensitive endogenous sialidase acts on a substrate other than GSLs to regulate antiviral immunity. For instance, it is known that activated T cells have increased sialidase activity and also have hyposialyated MHC class I molecules (12, 26). In our experimental system, oseltamivir treatment had no effect on ex vivo lung mononuclear cell sialidase activity induced by RSV infection (data not shown). The reasons for this are unclear but may be related to the relatively short half-life of the active form of the drug, the length of time it took to perform the ex vivo experiments, and/or extensive washing of the lung cells. Further studies will be required to define sialidase(s) and substrate(s) involved in oseltamivir-mediated inhibition of the antiviral response to RSV.

Inhibition of RSV clearance by oseltamivir treatment has implications for treating respiratory viral infections. Oseltamivir was developed as an influenza NA inhibitor based on x-ray crystal structures of influenza NA complexed with sialic acid (32). If oseltamivir inhibits a human endogenous sialidase that is important for T cell antiviral functions, we speculate that this anti-inflammatory effect could possibly prolong shedding of viruses that lack NA, such as RSV.


   Acknowledgments
 
We thank Dr. Barney Graham for critical review of the manuscript. We thank Dr. James Crowe for use of the fluorescence multiwell plate reader.


   Disclosures
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Grants HL069949, AI054660, and T32 GM07569, and American Academy of Allergy, Asthma, and Immunology Education and Research Trust Award. Back

2 Address correspondence and reprint requests to Dr. R. Stokes Peebles, Jr., T-1218 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2650. E-mail address: stokes.peebles{at}vanderbilt.edu Back

3 Abbreviations used in this paper: GSL, glycosphingolipid; RSV, respiratory syncytial virus; NA, neuraminidase; CtxB, cholera toxin B subunit; 4-MUNANA, 2'-(4-methylumbelliferyl)-{alpha}-D-N-acetylneuraminic acid; 4-MU, 4-methylumbelliferone; d.p.i., day postinfection; MFI, mean fluorescence intensity. Back

Received for publication October 12, 2006. Accepted for publication December 21, 2006.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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Right arrow Articles by Peebles, R. S., Jr.
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*Compound via MeSH
*Substance via MeSH

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